Recently, the availability of rAAV vectors based on distinct serotypes has provided natural substrates for defining mechanisms of efficient vector transduction. To advance the prospects of AAV gene delivery, vectors that specifically and efficiently target defined cell types without transducing others will be a major advancement and an eventual requirement for successful clinical application. One of the focuses of Project 3, will be related to understanding AAV serotype specific infection in order to design targeting vectors. Another focus of this proposal will be related to rate-limiting steps of vector re-administration. Although, AAV is characteristically known for long-term transgene expression, humoral immune response to primary AAV virion infection has been shown to prevent re-administration in animal models. In addition, the prevalence of serotype positive individuals in the population has been reported to be as high as 80% for AAV serotype 2. These two points will eventually have significant impact on the wide-spread use of AAV vectors in the general population. To approach this immunological problem, we will evaluate the ability to stealth AAV vectors using microemulsion polymer technology. The primary objective of Project 3 of this Program is to develop novel delivery systems that exploit the advantages of AAV viral infectivity and modify these reagents using novel microemulsion polymer chemistry in order to overcome blocks in vector re- administration.